Excitatory-Inhibitory Response to GABA-B Challenge Is Different in Adults with and without an Autism Spectrum Condition

Background: The underlying neurobiology of Autism Spectrum Conditions (ASC) is still poorly understood, but progress is being made. Multiple lines of research converge to suggest that there are alterations in glutamate (excitation, E) and gamma-aminobutyric acid (GABA) (inhibition, I) function, especially in the GABA system(Coghlan et al., 2012). For example, post-mortem abnormalities in GABA_B receptor expression [which regulates the release of both glutamate and GABA(Padgett and Slesinger, 2010)] have been reported in ASC (Fatemi et al., 2009). Our recent studies suggest that brain E-I responsivity differences in ASC can be detected in-vivo using proton magnetic resonance spectroscopy (¹H-MRS) (Ajram et al., 2017), however, no one has directly tested whether GABA_B receptors modulate E-I differently in autistic individuals compared to neurotypical individuals.

Objectives: In the current study we used ¹H-MRS HERMES (Saleh et al., 2016) to investigate the role of GABA_B receptors in the modulation of E-I after a single high or low oral dose of Arbaclofen, a GABA_B receptor agonist, compared to placebo in adult men with and without ASC.

Methods: Thirty-two adult men, half with ASC, were scanned on 3 different days at least 5 days apart to ensure complete drug washout. On each visit a single-dose of Arbaclofen (15mg or 30mg) or placebo was administered in a double-blinded, randomised order. ¹H-MRS data collection from the dorsomedial prefrontal cortex (DMPFC) and medial occipital cortex (mOCC) started 60 min after drug administration, corresponding to expected drug peak plasma levels. We computed the Glx/GABA+ (E-I) ratio (Glx = Glutamate + Glutamine; GABA+ = GABA + macromolecules) and used a repeated measures ANOVA to test group, drug, and group x drug interaction effects within each voxel.

Results: Group differences: There was no main effect of group in E-I measures in the DMPFC. There was a main effect of group (p=0.021) in the mOCC region; E-I was lower in the ASC group. Effect of drug: Arbaclofen shifted E-I in the DMPFC voxel in both groups (main effect of drug p=0.024). However, the direction of change was different in the two groups (interaction p=0.026). In controls, E-I was reduced by both the 15mg and 30mg doses compared to placebo; however, this E-I reduction only reached statistical significance at the higher dose (p=0.017). Conversely, in the ASD group, low dose Arbaclofen increased E-I above baseline; high dose Arbaclofen decreased E-I below baseline, thus E-I was significantly higher in the 15mg Arbaclofen condition compared to the 30mg condition (p=0.026). There was no drug effect or drug x group interaction in the mOCC voxel.

Conclusions: The responsivity of GABA_B receptor systems is atypical in ASC. Arbaclofen is currently being examined in Clinical Trials for ASC. Our finding that the effect of Arbaclofen in ASC is both dose and region dependent may have implications for dose selection and/or understanding how this target engagement relates to a longer-term treatment response.